US2832784A - Comparison of activities of piperazine - Google Patents
Comparison of activities of piperazine Download PDFInfo
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- US2832784A US2832784A US2832784DA US2832784A US 2832784 A US2832784 A US 2832784A US 2832784D A US2832784D A US 2832784DA US 2832784 A US2832784 A US 2832784A
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- piperazine
- ether
- added
- salts
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- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title description 22
- 230000000694 effects Effects 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 36
- 150000003839 salts Chemical group 0.000 description 24
- 239000011780 sodium chloride Substances 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- NSMWYRLQHIXVAP-UHFFFAOYSA-N 2,5-dimethylpiperazine Chemical compound CC1CNC(C)CN1 NSMWYRLQHIXVAP-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 14
- 239000000463 material Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 241000498255 Enterobius vermicularis Species 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 150000001450 anions Chemical class 0.000 description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000003000 nontoxic Effects 0.000 description 8
- 231100000252 nontoxic Toxicity 0.000 description 8
- 150000004885 piperazines Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 206010014881 Enterobiasis Diseases 0.000 description 6
- HKZLPVFGJNLROG-UHFFFAOYSA-M Silver chloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000004432 carbon atoms Chemical group C* 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- -1 dimethyl tosylate Chemical compound 0.000 description 6
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 230000000968 intestinal Effects 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 244000045947 parasites Species 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N Silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical class C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 4
- IBHWYGSDKUDDLN-UHFFFAOYSA-N 1,4-didodecyl-2,5-dimethylpiperazine Chemical compound CCCCCCCCCCCCN1CC(C)N(CCCCCCCCCCCC)CC1C IBHWYGSDKUDDLN-UHFFFAOYSA-N 0.000 description 2
- RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical class CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 description 2
- MYMSJFSOOQERIO-UHFFFAOYSA-N 1-bromodecane Chemical compound CCCCCCCCCCBr MYMSJFSOOQERIO-UHFFFAOYSA-N 0.000 description 2
- PBLNBZIONSLZBU-UHFFFAOYSA-N 1-bromododecane Chemical compound CCCCCCCCCCCCBr PBLNBZIONSLZBU-UHFFFAOYSA-N 0.000 description 2
- IKPSIIAXIDAQLG-UHFFFAOYSA-N 1-bromoundecane Chemical compound CCCCCCCCCCCBr IKPSIIAXIDAQLG-UHFFFAOYSA-N 0.000 description 2
- RSVLWLFDUXGXBR-UHFFFAOYSA-N 2,5-dimethylpiperazine;hydrochloride Chemical compound Cl.CC1CNC(C)CN1 RSVLWLFDUXGXBR-UHFFFAOYSA-N 0.000 description 2
- OSGLDZAYZRMKOK-UHFFFAOYSA-N CC1C([N+](CCN1CCCCCCCCCCCC)(CCCCCCCCCCCC)C)(C)C Chemical class CC1C([N+](CCN1CCCCCCCCCCCC)(CCCCCCCCCCCC)C)(C)C OSGLDZAYZRMKOK-UHFFFAOYSA-N 0.000 description 2
- 210000001198 Duodenum Anatomy 0.000 description 2
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
- 206010061217 Infestation Diseases 0.000 description 2
- 229940001447 Lactate Drugs 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N Nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 235000001188 Peltandra virginica Nutrition 0.000 description 2
- 244000197580 Poria cocos Species 0.000 description 2
- 235000008599 Poria cocos Nutrition 0.000 description 2
- MSFPLIAKTHOCQP-UHFFFAOYSA-M Silver iodide Chemical compound I[Ag] MSFPLIAKTHOCQP-UHFFFAOYSA-M 0.000 description 2
- 229940005581 Sodium Lactate Drugs 0.000 description 2
- NGSFWBMYFKHRBD-UHFFFAOYSA-M Sodium lactate Chemical compound [Na+].CC(O)C([O-])=O NGSFWBMYFKHRBD-UHFFFAOYSA-M 0.000 description 2
- 241000975692 Syphacia obvelata Species 0.000 description 2
- ULFCWDJTGXIGCJ-UHFFFAOYSA-M [Cl-].C(CCCCCCCCCCC)[N+]1(C(CN(C(C1)C)C)C)C Chemical compound [Cl-].C(CCCCCCCCCCC)[N+]1(C(CN(C(C1)C)C)C)C ULFCWDJTGXIGCJ-UHFFFAOYSA-M 0.000 description 2
- NBRJBROZOCSQBG-UHFFFAOYSA-M [Cl-].CC1C([N+](CCN1CCCCCCCCCCCC)(CCCCCCCCCCCC)C)(C)C Chemical compound [Cl-].CC1C([N+](CCN1CCCCCCCCCCCC)(CCCCCCCCCCCC)C)(C)C NBRJBROZOCSQBG-UHFFFAOYSA-M 0.000 description 2
- UPWMCZPXWOUFJB-UHFFFAOYSA-M [I-].C(CCCCCCCCCCC)[N+]1(C(CN(C(C1)C)C)C)C Chemical compound [I-].C(CCCCCCCCCCC)[N+]1(C(CN(C(C1)C)C)C)C UPWMCZPXWOUFJB-UHFFFAOYSA-M 0.000 description 2
- UDFMFXIHVCBKTI-UHFFFAOYSA-N [I-].CC1[NH2+]CC(NC1)C Chemical compound [I-].CC1[NH2+]CC(NC1)C UDFMFXIHVCBKTI-UHFFFAOYSA-N 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 230000001476 alcoholic Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 150000001860 citric acid derivatives Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 150000004694 iodide salts Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 2
- 150000003893 lactate salts Chemical class 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000005528 methosulfate group Chemical group 0.000 description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 230000036515 potency Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002035 prolonged Effects 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 231100000817 safety factor Toxicity 0.000 description 2
- 229940045105 silver iodide Drugs 0.000 description 2
- 229910001923 silver oxide Inorganic materials 0.000 description 2
- MLKQJVFHEUORBO-UHFFFAOYSA-M silver;methanesulfonate Chemical compound [Ag+].CS([O-])(=O)=O MLKQJVFHEUORBO-UHFFFAOYSA-M 0.000 description 2
- 239000001540 sodium lactate Substances 0.000 description 2
- 235000011088 sodium lactate Nutrition 0.000 description 2
- 229940066771 systemic antihistamines Piperazine derivatives Drugs 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
Definitions
- X- is the anion of a. nontoxic acid and R is a straight chain alkyl radical having l0l2 carbon atoms inclusive.
- piperazine is completely effective when given over a three-day period and removes large numbers of worms in even one dose.
- anion is of only subsidiary importance, the valuable properties residing in the cation.
- iodides were first prepared and when these were of interest, the chlorides or other salts were formed.
- Suitable salts are (further) methosulfates, phosphates, lactates, acetates, citrates, toluene sulfonates, etc.
- the most convenient route is to react 2,5-ditnethylpiperazine with two equivalents of RX (X being iodide, bromide or toluene sulfonate) to give an N,N-diR-2,5- dimethylpiperazine.
- methyl iodide is then reacted with excess methyl iodide to give a dimethiodide or with methyltoluenesulfonate to give a dimethyl tosylate, or with methyl sulfate to give a dimethosulfate.
- the iodide can be converted to the chloride by treatment with silver chloride or by warming with methanolic hydrogen chloride.
- Other salts can be prepared from those just mentioned by conventional methods.
- N,N'-bis-n-decyl-2,5-dimetkyl piperazine 57 g. of 2,5-dimethyl piperazine, 88 g. NaHCO 259 g. n-decyl bromide and l l. 95% ethanol were refluxed for 22 hours. Water was added to the mixture until all the salts dissolved, and the solution was concentrated in vacuo. The remaining oil was cooled and extracted twice with ether. The combined ether extracts were acidified with alcoholic hydrochloric acid and the dihydrochloride was filtered off and washed with ether. The resulting 191 g.
- N,N'-bz's-decyl, N,N'-bis-methyl, 2,5-dz'methyl piperazinium iodide N,N'-bis decyl, N,N'-bis methyl, 2,5-dimethylpiperazinium chloride 36.3 g. of N,N'-bis decyl, N,N'-bis methyl, 2,5-dimethylpiperazinium iodide was dissolved in 100 ml. of MeOH and 21.5 g. of freshly prepared silver chloride was added with stirring. After 3 hours the mixture was filtered, and the material evaporated almost to dryness. Several volumes of ether were added; the material was filtered E and recrystallized from methanol-ether to yield 26.0 g. of pure material melting at 235-237.
- N ,N -bis-n-zmdecyI-2,5 -dimethylpiperazine A mixture of 100g. of n-undecyl bromide, 22.8 g. 2,5-dimethylpiperazine, 35.7 g. of sodium bicarbonate and 600 ml. of ethanol was refiuxed with stirring for 14 hours. It was then cooled and filtered. The solvent was evaporated off in vacuo, and the residue was extracted with ether twice. Dry hydrogen chloride gas was bubbled through the ether solution until it was saturated. The dihydrochloride was filtered oil and washed with ether. It was then stirred with water and excess 45% NaOH to convert it to the base which was then extracted twice with benzene. The benzene was dried over K CO and then evaporated in vacuo, leaving the base as the residue.
- N,N'-bis-lmdecyl-N,N-bis methyl, 2,5-dimethylpl'perazinium iodide 71.5 g. of N,N-bis-undecyl 2,5-dimethyl piperazine, dissolved in 250 ml. of acetone and 50 ml. of dry benzene, was warmed and 64 g. of methyl iodide was added. The mixture in a tightly stoppered bottle was kept at 40-50 for two weeks. Four to five volumes of ether was then added and the precipitated solid filtered oil to yield 117 g. of crude crystalline residue. This, when recrystallized from nitromethane yielded material melting at 190-192.
- N ,N'-bis-undecyl-N,N '-bismethyl2,5 -dimcthylpiperazinium chloride 20 g. of N,N-bis-undecyl-N,N'-bismethyl-2,5-dimethyl piperazinium iodide was dissolved in 50 ml. of absolute methanol and 17 g. of freshly prepared silver chloride was added. The mixture was stirred for 3 hours, filtered, and the filtrate evaporated almost to dryness. Several volumes of ether were added and the material was filtered ofi. Recrystallization from methanol-ether yielded 14 g. of solid melting at 234-236".
- N,N'-bis-n-dodecyl-2,5-dimethyl piperazine A mixture of 57 g. of 2,5-dimethyl piperazine, 299 g. of n-dodecyl bromide, 100 g. of sodium bicarbonate and l l. of EtOH was heated under reflux with stirring for 16 hours. The bulk of the alcohol was then evaporated in vacuo, and about 500 m1. of water was added to dissolve the salts that precipitated. The aqueous solution was brought to pH 7 with aqueous hydrochloric acid (foaming) and an additional 750 ml. of 4 N aqueous hydrochloric acid was added.
- the resulting precipitate of the dihydrochloride of the product was filtered off, washed with water and then with low-boiling petroleum ether. It was then suspended in benzene and converted to the base by addition of an excess of aqueous sodium hydroxide solution with efficient stirring.
- the productbase, in benzene solution was dried over sodium hydroxide pellets, and the benzene evaporated off.
- the residue solidified, and was recrystallized from 1 l. of pentane (Skellysolve A) by cooling to C. overnight. The crystals melted at 50-52 C., and weighed 144 g. Additional crops could be obtained from the mother liquors by partial evaporation of solvent and cooling.
- N ,N '-bis-d0decyl-N ,N '-bis-methyl-2,5-dimethylpiperazinium chloride 20 g. of N,N'-bis-dodecyl,N,N-bis-methyl-2,S-dimethylpiperazinium iodide was dissolved in 160 ml. of methanol and dry HCl gas was passed into the solution, maintained at its boiling point for /2 hour. The solution was then evaporated almost to dryness and ether added until no more material precipitated. The resulting crystals were recrystallized from methanol-ether. The yield was 14.7 g., M. P. 249-250" dec.
- N,N'-bis-dodecyl-N,N'-bis-methyl-2,5-dimethylpiperazinz'um lactate 9.8 g. N,N bis dodecyl N,N' bis methyl 2,5- dimethylpiperazinium chloride was dissolved in 30 ml. absolute ethanol, and a solution of 4.03 g. sodium lactate in 30 ml. abs. ethanol was added. The mixture was cooled and 5 ml. of dry benzene was added. The sodium chloride that precipitated was filtered off after 3 hours and the tilt-rate was evaporated to dryness. Yield 11.3 g, M. P. 168-173.
- 1,4-bis-d0decyl-1,2,4,S-tetramethylpiperazinium methanesulfonate Silver methanesulfonate was prepared from equivalent amounts of silver oxide and methanesulfonic acid in water. One gram of 1,4 bis dodecyl 1,2,4,5 tetramethylpiperazinium iodide dissolved in methanol was added to 650 mg. of silver methanesulfonate dissolved in 100 ml. of hot methanol. After filtration to remove silver iodide, the solvent was evaporated to leave 1.1 g. of the above-named methanesulfonate, which darkened ca. 220 and charred ca. 260 without melting.
- R is a straight-chain alkyl radical containing 10-12 carbon atoms
- X'- is the anion of a nontoxic acid
- a process for the elimination of intestinal worms which comprises the administration of a compound having the formula R on r flv car w a wherein R is a straight-chain alkyl radical containing 10-12 carbon atoms, and X- is the anion of a nontoxic acid.
Description
United tates Patent AN'I'HELit-HNTIC PIPERAZINES Norton Harfenist, Yonkers, and Ernest G. Magnien, Flushing, N. Y., nssignors to Burroughs Wellcome & Co. (U. S. A.) ind, Tuckahoe, N. Y., a corporation of New York No Drawing. Application June 11, 1956 Serial No. 590,367
4 Claims. (Cl. 260-268) The subject of the present invention relates to a family of diquaternary salts derived from 2,5-dimethylpiperazine. The general formula is:
wherein X- is the anion of a. nontoxic acid and R is a straight chain alkyl radical having l0l2 carbon atoms inclusive.
These compounds have exceptional activity against intestinal worms and particularly against pinworms. Human pinworm infestations are extremely diiiicult to combat and are widespread even among highly civilized populations. The drug of choice at present is piperazine, which is inexpensive and virtually nontoxic. its use has only one major disadvantage. The treatment extends over a long period of time, days to 3 weeks, and thus involves a number of inconveniences especially as the simultaneous treatment of an entire family is generally advisable to prevent reinfection.
Such prolonged treatment with piperazine is believed to be necessary because pinworms inhabit the lower part of the intestinal tract and the drug, which is extensively absorbed, does not arrive at the site of its action in a high concentration. Against Ascarz's litmbricoides, which dwells in the duodenum, piperazine is completely effective when given over a three-day period and removes large numbers of worms in even one dose.
Since quaternary ammonium salts of large size are not readily absorbed from the gut, it was hoped that piperazine quaternary salts might be more eitective. To some extent this is true, and a family of piperazine monoquaternary salts forms the subject of a copending application. Along with the monoquaternary salts, a variety of diquaternary salts were prepared not only from piperazine butalso from several C-substituted piperazines, although these compounds as the simple bases are uniformly less efiective for this purpose than is piperazine.
2,832,784 Patented Apr. 29, 1958 ice Of the C-substituted pipera'zines examined, thereadily available 2,5-dimethylpiperazine offered derivatives of the greatest interest. In the table are shown the potencies and toxicities of some of these in comparison with those of the corresponding piperazine derivatives. Quaternary salts of both series having values for R higher or lower than those shown have only minor interest. The toxicities (LD-SO) and activities were both determined on mice, the latter on mice infested with the pinworm Syphacia obvelata which is closely related to the human pinworm, and has been shown to be a reliable guide in these investigations (cf. Kam-Fai Chan, Am. J. Hyg. 56, 22 (1952); Paul E. Thompson and J. S. Reinertson, Exper. Parasit. 1, 384 (1952); H. W. Brown, K-F Chan and B. D. Ferrell, Exper. Parasit. 3, 45 (1954)). The dose is that given on each of two successive days and the percent of worms removed is based on the wormburden of treated mice compared to that of control mice infected at the same time and in the same fashion- It will be seen that in each series there is a peaking of the activity at some middle value of R (a very common phenomenon in biological work) and that most surprisingly the optimum value for R is higher in the 2,5-dimethylpiperazine series (R=l2) than in the common piperazine series (R=1012) despite the fact that the same figure for R gives a higher molecular weight in the former case. At the same time the toxicity to the host of the dimethylpiperazine series is appreciably less (LD-SO values higher) than in the normal series-giving a larger safety factor highly desirable in general and especially when dealing with an ailment of a nonlethal though annoying nature.
The nature of the anion, X, is of only subsidiary importance, the valuable properties residing in the cation. Most frequently the iodides were first prepared and when these were of interest, the chlorides or other salts were formed. Suitable salts are (further) methosulfates, phosphates, lactates, acetates, citrates, toluene sulfonates, etc. The most convenient route is to react 2,5-ditnethylpiperazine with two equivalents of RX (X being iodide, bromide or toluene sulfonate) to give an N,N-diR-2,5- dimethylpiperazine. This is then reacted with excess methyl iodide to give a dimethiodide or with methyltoluenesulfonate to give a dimethyl tosylate, or with methyl sulfate to give a dimethosulfate. The iodide can be converted to the chloride by treatment with silver chloride or by warming with methanolic hydrogen chloride. Other salts can be prepared from those just mentioned by conventional methods.
An alternative preparation is by treating 2,5-dimethylpiperazines with formalin and formic acid (Clarke- Eschweiler procedure) to give 1,2,4,5,-tetramethylpiperazine which is then quaternized with the higher halide, usually the bromide. In general, this is less convenient since the reaction time for the quaternization step becomes inconveniently long.
COMPARISON OF ACTIVITIES OF PIPERAZINE AND 2,5-DIMETHYLPIPERAZINE DERIVATIVES R R R R -LD-50, Dose, Percent LD-50, Percent R X rug/kg. mgjkg. worms X mg./kg org/kg. worms removed removed 08H 1 200 34 1 gg 01 300 45 can. I 3,700 3% 2g 1 3,000 23 0,111 r 3,000 383 g 1 4,000 33g 400 100 200 99 can" I 5,500 23 r 8,000 288 92 500 100 01 8,000 $28 3 100 60 013E" I 4, 000 500 82 014B" I a, 700 1, 200 90 A still further advantage of these diquaternary salts is that they damage the parasites irreversibly while piperazine merely paralyzes them. Usually the worms are expelled while helpless, but if any are not, they are able to continue their life normally after treatment with piperazine.
N,N'-bis-n-decyl-2,5-dimetkyl piperazine 57 g. of 2,5-dimethyl piperazine, 88 g. NaHCO 259 g. n-decyl bromide and l l. 95% ethanol were refluxed for 22 hours. Water was added to the mixture until all the salts dissolved, and the solution was concentrated in vacuo. The remaining oil was cooled and extracted twice with ether. The combined ether extracts were acidified with alcoholic hydrochloric acid and the dihydrochloride was filtered off and washed with ether. The resulting 191 g. of the dihydrochloride was suspended in water, made strongly basic with 45% NaOH, and extracted twice with benzene. The benzene extracts were evaporated in vacuo. Ether and pentane were added and the solution cooled and filtered, to give 116 g. of crystalline base, M. P. 119-121".
N,N'-bz's-decyl, N,N'-bis-methyl, 2,5-dz'methyl piperazinium iodide N,N'-bis decyl, N,N'-bis methyl, 2,5-dimethylpiperazinium chloride 36.3 g. of N,N'-bis decyl, N,N'-bis methyl, 2,5-dimethylpiperazinium iodide was dissolved in 100 ml. of MeOH and 21.5 g. of freshly prepared silver chloride was added with stirring. After 3 hours the mixture was filtered, and the material evaporated almost to dryness. Several volumes of ether were added; the material was filtered E and recrystallized from methanol-ether to yield 26.0 g. of pure material melting at 235-237.
N ,N -bis-n-zmdecyI-2,5 -dimethylpiperazine A mixture of 100g. of n-undecyl bromide, 22.8 g. 2,5-dimethylpiperazine, 35.7 g. of sodium bicarbonate and 600 ml. of ethanol was refiuxed with stirring for 14 hours. It was then cooled and filtered. The solvent was evaporated off in vacuo, and the residue was extracted with ether twice. Dry hydrogen chloride gas was bubbled through the ether solution until it was saturated. The dihydrochloride was filtered oil and washed with ether. It was then stirred with water and excess 45% NaOH to convert it to the base which was then extracted twice with benzene. The benzene was dried over K CO and then evaporated in vacuo, leaving the base as the residue.
N,N'-bis-lmdecyl-N,N-bis methyl, 2,5-dimethylpl'perazinium iodide 71.5 g. of N,N-bis-undecyl 2,5-dimethyl piperazine, dissolved in 250 ml. of acetone and 50 ml. of dry benzene, was warmed and 64 g. of methyl iodide was added. The mixture in a tightly stoppered bottle was kept at 40-50 for two weeks. Four to five volumes of ether was then added and the precipitated solid filtered oil to yield 117 g. of crude crystalline residue. This, when recrystallized from nitromethane yielded material melting at 190-192.
N ,N'-bis-undecyl-N,N '-bismethyl2,5 -dimcthylpiperazinium chloride 20 g. of N,N-bis-undecyl-N,N'-bismethyl-2,5-dimethyl piperazinium iodide was dissolved in 50 ml. of absolute methanol and 17 g. of freshly prepared silver chloride was added. The mixture was stirred for 3 hours, filtered, and the filtrate evaporated almost to dryness. Several volumes of ether were added and the material was filtered ofi. Recrystallization from methanol-ether yielded 14 g. of solid melting at 234-236".
N,N'-bis-n-dodecyl-2,5-dimethyl piperazine A mixture of 57 g. of 2,5-dimethyl piperazine, 299 g. of n-dodecyl bromide, 100 g. of sodium bicarbonate and l l. of EtOH was heated under reflux with stirring for 16 hours. The bulk of the alcohol was then evaporated in vacuo, and about 500 m1. of water was added to dissolve the salts that precipitated. The aqueous solution was brought to pH 7 with aqueous hydrochloric acid (foaming) and an additional 750 ml. of 4 N aqueous hydrochloric acid was added. The resulting precipitate of the dihydrochloride of the product was filtered off, washed with water and then with low-boiling petroleum ether. It was then suspended in benzene and converted to the base by addition of an excess of aqueous sodium hydroxide solution with efficient stirring. The productbase, in benzene solution, was dried over sodium hydroxide pellets, and the benzene evaporated off. The residue solidified, and was recrystallized from 1 l. of pentane (Skellysolve A) by cooling to C. overnight. The crystals melted at 50-52 C., and weighed 144 g. Additional crops could be obtained from the mother liquors by partial evaporation of solvent and cooling.
N ,N '-bis-d0decyl-N ,N '-bis-methyl-2,5-dimethylpiperazinium chloride 20 g. of N,N'-bis-dodecyl,N,N-bis-methyl-2,S-dimethylpiperazinium iodide was dissolved in 160 ml. of methanol and dry HCl gas was passed into the solution, maintained at its boiling point for /2 hour. The solution was then evaporated almost to dryness and ether added until no more material precipitated. The resulting crystals were recrystallized from methanol-ether. The yield was 14.7 g., M. P. 249-250" dec.
N,N'-bis-dodecyl-N,N'-bis-methyl-2,5-dimethylpiperazinz'um lactate 9.8 g. N,N bis dodecyl N,N' bis methyl 2,5- dimethylpiperazinium chloride was dissolved in 30 ml. absolute ethanol, and a solution of 4.03 g. sodium lactate in 30 ml. abs. ethanol was added. The mixture was cooled and 5 ml. of dry benzene was added. The sodium chloride that precipitated was filtered off after 3 hours and the tilt-rate was evaporated to dryness. Yield 11.3 g, M. P. 168-173.
1,4-bis-d0decyl-1,2,4,S-tetramethylpiperazinium methanesulfonate Silver methanesulfonate was prepared from equivalent amounts of silver oxide and methanesulfonic acid in water. One gram of 1,4 bis dodecyl 1,2,4,5 tetramethylpiperazinium iodide dissolved in methanol was added to 650 mg. of silver methanesulfonate dissolved in 100 ml. of hot methanol. After filtration to remove silver iodide, the solvent was evaporated to leave 1.1 g. of the above-named methanesulfonate, which darkened ca. 220 and charred ca. 260 without melting.
What we claim is:
1. A compound having the formula:
wherein R is a straight-chain alkyl radical containing 10-12 carbon atoms, and X'- is the anion of a nontoxic acid.
2. A 1,2,4,5 tetramethyl 1,4 bis-dodecylpiperazinium salt.
3. 1,2,4,5 tetramethyl 1,4 bis dodecylpiperazinium chloride.
4. A process for the elimination of intestinal worms which comprises the administration of a compound having the formula R on r flv car w a wherein R is a straight-chain alkyl radical containing 10-12 carbon atoms, and X- is the anion of a nontoxic acid.
References Cited in the file of this patent UNITED STATES PATENTS Baltzly et a1. July 17, 1956 OTHER REFERENCES Smith et a1.: Jour. Am. Chem. Soc., vol. 72, pp. 2969- (1950).
Claims (1)
1. A COMPOUND HAVING THE FORMULA:
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3063880A (en) * | 1959-03-13 | 1962-11-13 | Pennsalt Chemicals Corp | Propellants containing n, n'-dialkyltriethylene-diammonium dinitrates |
US3167561A (en) * | 1963-02-05 | 1965-01-26 | Merck & Co Inc | 2, 5-diazabicyclo-[2,2,1]heptanes and [2,2,2]octanes |
US3232941A (en) * | 1959-03-13 | 1966-02-01 | Pennsalt Chemicals Corp | N,n'-dialkyltriethylenediammonium dinitrates |
Citations (1)
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US2755279A (en) * | 1956-07-17 | I-alkyl z |
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- US US2832784D patent/US2832784A/en not_active Expired - Lifetime
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US2755279A (en) * | 1956-07-17 | I-alkyl z |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3063880A (en) * | 1959-03-13 | 1962-11-13 | Pennsalt Chemicals Corp | Propellants containing n, n'-dialkyltriethylene-diammonium dinitrates |
US3232941A (en) * | 1959-03-13 | 1966-02-01 | Pennsalt Chemicals Corp | N,n'-dialkyltriethylenediammonium dinitrates |
US3167561A (en) * | 1963-02-05 | 1965-01-26 | Merck & Co Inc | 2, 5-diazabicyclo-[2,2,1]heptanes and [2,2,2]octanes |
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